DESCRIPTION (Applicant's abstract): It has been known for many years that high resistance exercise results in the hypertrophy of skeletal muscle, however, to date very little is known about the signaling mechanisms regulating this growth response. Studies of exercise-induced hypertrophy in mammals have shown that an early response to one bout of exercise is a transient increase in protein synthesis followed by subsequent increases in muscle specific mRNAs. This pattern of change suggests a model in which the transient increase in protein synthesis produces specific factors important for muscle growth. The overall aims of this project are to elucidate the upstream signaling mechanism(s) necessary for protein synthesis changes following resistance exercise and to determine the role of translational activation in the development of skeletal muscle hypertrophy. We have modified an in vivo model to study the regulation of exercise-stimulated protein synthesis. With this model, the phosphorylation of p70s6k was identified a an acute marker of the hypertrophic growth response. This provides a critical starting point from which experiments have been designed to delineate the growth- related signaling pathways stimulated by exercise. We also have found that p70s6k is activated following stretch-induced growth of myotubes in vitro. The experiments proposed rely on the use of in vitro stretch system to screen for the critical factors and pathways activated. These factors and pathways will subsequently be tested for their physiological significance in vivo. The findings from this project are important for the basic understanding of how striated muscle cells regulate their size in response to increased loading. In addition, the results from these studies have tremendous application for the fields of aging and rehabilitation. Age-associated muscle atrophy is a debilitating condition that can decrease the quality of life as well as limit independent living for the elderly. Understanding the factors and pathways that regulate the growth response of skeletal muscle will be important for designing therapeutic treatments (pharmacological or exercise based) to attenuate or reverse losses in muscle mass.